What does this research mean for the field?

The molecular glue PRLX-93936 triggers nuclear pore complex degradation by forming a composite surface with TRIM21 that binds NUP98 with minimal direct small molecule-NUP98 contacts, a mechanism that enables structurally diverse ligands to induce degradation and allows for the development of enhanced glues like MAN-021. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

The research investigates how the molecular glue PRLX-93936 alters TRIM21's function to induce nuclear pore degradation.

May 29, 2026Open Access

The molecular basis for nuclear pore destruction by a proximity-inducing molecular glue

Key Points

The research investigates how the molecular glue PRLX-93936 alters TRIM21's function to induce nuclear pore degradation.
Utilized biochemical assays to evaluate TRIM21's binding with NUP98 and substrate specificity changes.
Characterized the structural basis for NUP98 recognition through ternary complex analysis.
Developed enhanced molecular glue MAN-021 and performed structural assessment.
PRLX-93936 effectively induced degradation of nuclear pore complex targeting NUP98 through TRIM21 interaction.
Ternary complex formation was shown to depend on specific binding sites for NUP98, influenced by PRLX.
The newly identified MAN-021 exhibited superior structural properties and potential for improved therapeutic application.

Abstract

Summary Molecular glues that induce new protein interactions can be potent therapeutics. We and others recently discovered that the small molecule PRLX-93936 (PRLX), which was originally developed as an erastin derivative with antitumor activity, is a molecular glue that alters the substrate specificity of the TRIM21 ubiquitin ligase. PRLX causes TRIM21 to bind the nuclear pore protein NUP98, triggering nuclear pore complex (NPC) degradation. We present here the structural and biochemical basis of NUP98 recognition, finding that ternary complex assembly depends on the creation of a composite TRIM21-small molecule surface competent for NUP98 binding. A scarcity of direct small molecule-NUP98 contacts likely explains how multiple structurally diverse TRIM21 ligands can induce NPC degradation. We also report the discovery of an enhanced molecular glue, MAN-021, and describe its structure. Our findings provide a basis for rational development of next-generation small molecules with enhanced or differentiated activities.

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